There are a number of vision-threatening disorders of the eye for which there are presently no good therapies. One major problem in treatment of such diseases is the inability to deliver therapeutic agents into the eye and maintain them there at therapeutically effective concentrations.
Oral ingestion of a drug or injection of a drug at a site other than the eye can provide a drug systemically. However, such systemic administration does not provide effective levels of the drug specifically to the eye. In many opthalmologic disorders involving the retina, posterior tract and optic nerve, adequate levels of drug cannot be achieved or maintained by oral or parenteral routes of administration. Further, repeated administration of the drug may be necessary to achieve these concentrations. However, this may produce undesired systemic toxicity. For example, subcutaneously or intramuscularly administered interferon-.alpha. in adults may result in complications such as flu-like symptoms with fatigue, anorexia, nausea, vomiting, thrombocytopenia, and leukopenia.
Ophthalmic conditions have also been treated using drugs applied directly to the eye in either liquid or ointment form. This route of administration however is only effective in treating problems involving the superficial surface of the eye and diseases which involve the cornea and anterior segment of the eye. Topical administration of drugs is ineffective in achieving adequate concentrations of drug in the sclera, vitreous or posterior segment of the eye. In addition, topical eye drops may drain from the eye through the nasolacrimal duct and into the systemic circulation, further diluting the medication and risking unwanted systemic side effects. Furthermore, the drug is administered indiscriminately to all tissue compartments of the eye, including those that may not need the medication and may in fact suffer unwanted side effects to the drug.
Delivery of drugs in the form of topical eye drops is also of little utility when the drug is a protein or peptide that lacks the ability to cross the cornea and be made available to the vitreous, retina or other subretinal structures such as the retinal pigment epithelium ("RPE") or choroidal vasculature. In addition, many proteins or peptides are highly unstable and are therefore not easily formulated for topical delivery.
Direct delivery of drugs into the eye by topical insert has also been attempted. However, this method is not desirable. Topical inserts require patient self-administration and thus education on insertion and removal. This demands a certain degree of manual dexterity, which can be problematic for geriatric patients. In many instances such inserts may cause eye irritation. These devices are prone to inadvertent loss due to lid laxity. These devices provide drug only to the cornea and anterior chamber, and do not provide any pharmacologic advantage over eye drops.
Another extraocular insert is a contact lens delivery system that releases medication over an extended period. See, e.g., JAMA, 260:24, p. 3556 (1988). The lens generally only lasts for a matter of hours or days before dissolving or releasing all of the therapeutic compound. Continuous delivery of medication is inconvenient, requiring frequent re-application. Again, these contact lenses only provide drug to the cornea and anterior chamber.
In rare cases, direct delivery of drugs has also been accomplished using externalized tubes. This requires insertion of one end of a tube into the corner of the patient's eye. The other end of the tube is taped to the patient's forehead and terminates in a septum, through which medication is delivered. This method is undesirable, being both uncomfortable and inconvenient. Since medication must be injected through the septum, the device is incapable of continuous delivery of medication. Furthermore, such tubes may become infected and in some cases ultimately threaten the patient's vision.
Direct delivery of drugs can also be accomplished by the intraocular injection of the drug, or microspheres that contain the drug. Microspheres migrate within the eye, either into the visual axis, or into adjacent tissue sites.
Most previous intraocular inserts for direct delivery of drugs into the eye have been unsuccessful either because they are unsuitable for long-term use or are uncomfortable to use. For example, the ocular device disclosed in U.S. Pat. No. 3,828,777 is not anchored into position, thus causing pain, irritation, foreign body sensation, retinal detachments and watering when the device moves. Other ocular inserts disclosed in patents do not disclose sizes or shapes that would allow long-term retention of the insert. See e.g., U.S. Pat. No. 4,343,787; U.S. Pat. No. 4,730,013; U.S. Pat. No. 4,164,559. Even in patents asserting an improved retention and prolonged period of use, the contemplated period is measured in days, such as 7 to 14 days. See, e.g., U.S. Pat. No. 5,395,618.
One intraocular insert is currently available for delivery of ganciclovir to the eye. Known as Vitrasert, the device consists of a nonerodable polymer-based sustained-release package containing ganciclovir, a non-proteinaceous nucleoside analog. The device is surgically implanted in the posterior of the eye (in the vitreous) to treat cytomegalovirus retinitis. See, e.g., Anand, R., et al., Arch. Ophthalmol., 111, pp. 223-227 (1993).
However, release of proteins from such a device (or other erodable or nonerodable polymers) cannot be sustained for anything longer than short periods of time due to protein instability. Accordingly, the Vitrasert device is unsuitable for long-term delivery of most, if not all, protein molecules.
Clinical treatment for retinal and choroidal neovascularization includes destruction of new vessels using photocoagulation or cryotherapy. However, side effects are numerous and include failure to control neovascularization, destruction of macula and central vision and decrease in peripheral vision. See, e.g., Aiello, L. P., et al., PNAS, 92, pp. 10457-10461 (1995).
A number of growth factors show promise in the treatment of ocular disease. For example, BDNF, and CNTF have been shown to slow degeneration of retinal ganglion cells and decrease degeneration of photoreceptors in various animal models. See, e.g., Genetic Technology News, vol. 13, no. 1 (Jan. 1993). Nerve growth factor has been shown to enhance retinal ganglion cell survival after optic nerve section and has also been shown to promote recovery of retinal neurons after ischemia. See, e.g., Siliprandi, et al., Invest. Ophthalmol. & Vis. Sci., 34, pp. 3232-3245 (1993).
Direct injection of neurotrophic factors to the vitreous humor of the eye has been shown to promote the survival of retinal neurons and photoreceptors in a variety of experimentally induced injuries as well as inherited models of retinal diseases. See, e.g., Faktorovich et al., Nature, vol. 347 at 83 (Sep. 6, 1990); Siliprandi et al., Investigative Ophthalmology and Visual Science, 34, p. 3222 (1993); LaVail et al., PNAS, 89, p. 11249 (1992); Faktorovich et al., Nature, 347, pp. 83-86 (1990).
However, previous methods of delivery of such neurotransmitters, growth factors, and neurotrophic factors have significant drawbacks. Some problems stem from the fact that growth factors do not cross the blood brain barrier well and are readily degraded in the blood stream. Further, problems arise with direct injection into the vitreous. For example, direct injection of bFGF resulted in an increased incidence of retinal macrophages and cataracts. See LaVail, PNAS, 89, p. 11249 (1992).
Accordingly, delivery of biologically active molecules to the eye without adverse effects remains a major challenge.